There is a critical need to identify biological factors that underlie differences in clinical presentation and response to treatment in asthma and chronic obstructive pulmonary disease (COPD). The growing recognition of heterogeneity in disease progression, outcomes, and burden of symptoms in combination with mounting evidence of an important link between the airway microbiome and the immunologic milieu of the airways continues to highlight new avenues of investigation. Current evidence supports distinguishing asthma patients by two immunological phenotypes ?broadly, those with elevated type 2 cytokine profiles and numbers of sputum eosinophils (T2-high) and those without (T2-low). While immunologic features that delineate COPD phenotypes are less clear, recent evidence suggests a T2-high subtype in addition to the traditionally T2-low phenotype. Our overall hypothesis is that distinct patterns of lower airway microbiota composition and function differentiate T2- high and T2-low inflammation in asthma, with shared microbial features present in the T2-low phenotypes of asthma and COPD.Therefore, the objectives of this project are to 1) Define airway microbiome features associated with T2-low asthma phenotype, and 2) Define features of the airway microbiome associated with clinical characteristics of asthma and COPD severity within the context of T2-low inflammation. In Aim 1, we propose to determine the specific members of the airway microbiota and features of their functional potential that associate with T2-low vs. T2-high inflammation in asthma using samples from 3 independent adult asthma cohorts. Our working hypotheses are 1) Compositional and functional features of sputum microbiota, particularly involving members of the Gammaproteobacteria, are differentially enriched in T2-low asthma and associate with clinical characteristics of asthma in T2-low subjects. 2)Non-bacterial members of the sputum microbiome, particularly fungi, are differentially enriched in T2-high asthma and associate with clinical characteristics of asthma in T2-high subjects. In Aim 2, we propose to determine the specific members of the airway microbiota and features of their functional potential that differentially associate with T2-low vs. T2-high inflammation in both asthma and COPD using combined data from both diseases. Our working hypothesis is that both T2-low asthma and T2-low COPD associate with similar compositional and functional features of the sputum bacterial microbiome, involving Proteobacteria members in particular. This project will significantly advance our current understanding of the clinical implications of airway microbial dysbiosis in T2-low asthma, and the contributions of the airway microbiota to COPD phenotype. It will also provide novel insight into the viral, fungal, and functional associations with asthma and COPD phenotype.